Immunological Priming to Hepatitis B Virus The hepatitis B virus (HBV) is a noncytopathic, enveloped, double-stranded DNA virus that causes acute and chronic hepatitis, and hepatocellular carcinoma (HCC). More than 350 million people are chronically infected by HBV which causes 1 million deaths each year worldwide, and no cure or reliable treatment currently exists. The HBV specific CD8 T cell response contributes to the pathogenesis of liver disease and viral clearance, and the failure to induce and/or sustain a vigorous CD8 T cell response results in viral persistence and triggers a cascade of chronic necroinflammatory process, ultimately leading to HCC. Thus, the long-term objective of this application is to delineate the mechanisms that regulate the quality and magnitude of CD8 T cell response to HBV. By adoptively transferring HBV-specific memory CD8 T cells into HBV transgenic mice, we have shown that the noncytolytic and cytolytic effector functions of the T cells are induced in an oscillatory manner as a consequence of intrahepatic antigen recognition. The finings, however, may not reflect what occurs in an immunologically naove host during HBV infection since they reflect the impact of antigen recognition by memory T cells. It has not been possible to analyze the early immunological events that occur during the priming of HBV-specific CD8 T cells due to the limitations of available models of HBV infection. Accordingly, the Chisari laboratory has recently generated T cell receptor (TCR) transgenic mice that have CD8 T cells specific for the HBV core and envelope proteins. Preliminary data suggest that, if HBV gene expression precedes the generation of HBV specific T cell precursors as it does during neonatal HBV infection, T cell priming occurs in the liver and the intrahepatic T cell priming induces functionally defective T cell responses. Building on these preliminary data, we will further define intrahepatic T cell priming events and elucidate the mechanisms responsible for the defective CD8 T cell responses. We will then determine whether and how the timing and magnitude of intrahepatic antigen expression regulate the CD8 T cell response to HBV. Finally, we will attempt to break peripheral tolerance in HBV transgenic mice as models for immunotherapy of chronic HBV infection. These studies are likely to provide novel and important insights into previously unknown early immunological events that occur in response to HBV infection in man. In addition, the knowledge gained from this grant application could help us develop new therapeutic strategies to terminate persistent infection. PUBLIC HEALTH RELEVANCE: Over 350 million people throughout the world are chronically infected by HBV, approximately 1.5 million of whom live in the United States. Death from cirrhosis of the liver and liver cancer occurs in 15-25% of chronically infected persons. The studies described in this proposal will improve understanding of the biology of this virus, and they may provide new information to help us develop new therapeutic strategies to terminate persistent infection and its attendant costs and complications.